Eudragit�: a technologyevaluationSeema Thakral, Naveen K Thakral & Dipak K Majumdar††University of Delhi, Delhi Institute of Pharmaceutical Sciences and Research (Formerly College of
Pharmacy), Department of Pharmaceutics, New Delhi, India
Introduction: Eudragit is the brand name for a diverse range of polymethacry-
late-based copolymers. It includes anionic, cationic, and neutral copolymers
based on methacrylic acid and methacrylic/acrylic esters or their derivatives.
Areas covered: In this review, the physicochemical characteristics and appli-
cations of different grades of Eudragit in colon-specific/enteric-coated/
sustained release drug delivery and taste masking have been addressed.
Expert opinion: Eudragits are amorphous polymers having glass transition
temperatures between 9 to > 150oC. Eudragits are non-biodegradable, non-
absorbable, and nontoxic. Anionic Eudragit L dissolves at pH > 6 and is used
for enteric coating, while Eudragit S, soluble at pH > 7 is used for colon targe-
ting. Studies in human volunteers have confirmed that pH drops from 7.0 at
terminal ileum to 6.0 at ascending colon, and Eudragit S based systems some-
times fail to release the drug. To overcome the shortcoming, combination of
Eudragit S and Eudragit L which ensures drug release at pH < 7 has been advo-
cated. Eudragit RL and RS, having quaternary ammonium groups, are water
insoluble, but swellable/permeable polymers which are suitable for the
sustained release film coating applications. Cationic Eudragit E, insoluble at
pH ‡ 5, can prevent drug release in saliva and finds application in
Eudragit is the brand name for a diverse range of copolymers based on polymetha-crylates principally marketed by Evonik Industries, Germany. Eudragit was firstintroduced by Rohm & Hass GmbH, Darmstadt in 1953 as an alkaline solubledrug coating material resistant to stomach acid. The brand has gradually diversifiedto include anionic, cationic as well as neutral copolymers based on methacrylic acidand methacrylic or acrylic esters or their derivatives in varying proportions, andthese copolymers exhibit varying degree of pH dependent/independent solubilityprofiles. In addition to being extensively used for functional pharmaceuticalcoatings, Eudragits are applied as matrix formers in common granulationtechniques as well as in direct compression.
2. Types of Eudragit
Eudragits are synthetic polymers obtained by polymerization of acrylic acid (prop-2-enoic acid; CH2=CHCOOH) and methacrylic acids or their esters like butyl esteror dimethylaminoethyl ester. Being synthetic polymers, Eudragits are supplied inextensively reproducible forms, in comparison to cellulosic derivatives, whosephysicochemical properties may vary depending on the source of raw material.Methacrylate copolymers are synthesized via free-radical polymerization, wherein
various acrylate and methacrylate derivatives are incorporatedinto the polymer by chain grow reactions [1]. (Figure 1) Thepolymerization reaction can be performed in solvent, bulk,suspension, or emulsion. Variations in chain length areobtained via various termination and transfer reactions. Thefunctional properties of methacrylate copolymers and thefinal polymer can be adjusted by selecting from a variety ofmonomers. The non-functional co-monomers are responsiblefor steering the polymer properties, and the functionalco-monomer for adjusting the solution profile [2].The basic chemical structure of Eudragit and its different
grades is presented in Figure 2. Different grades of Eudragitare commercially available and these are supplied in variousforms such as dry powder, granules, aqueous dispersion, ororganic solution. A (60:40) mixture of acetone and isopropa-nol is most commonly used as the organic solvent [3]. Thechemical nature, characteristic features, and applications ofdifferent types of Eudragit have been compiled in Table 1.The table shows that four broad classes of Eudragit are avail-able: cationic Eudragit E (soluble below pH 5.5) has applica-tion in taste masking; anionic Eudragit L and S (soluble abovepH 6 and 7, respectively) are used in colon targeting/entericcoating; neutral types Eudragit RL and RS (pH-independentsolubility) as well as Eudragit NE and NM (swellable andpermeable) are used in sustained release drug delivery.
In addition to all these popular grades, some lesser knowngrades of Eudragit include Eudragit P4135, a methacrylicacid, methyl acrylate, and methyl methacrylate copolymer(ratio of the functional groups 25:10:65), though its aqueousdispersion is used as Eudragit FS 30 D. Eudragit RD 100,which is comprised of 91% Eudragit RL PO and 9% carboxymethyl cellulose (the inclusion of latter increasing its perme-ability), is used as pH-independent coating material for fastdisintegrating films.
3. Background and characterization
3.1 Chemistry of EudragitMethacrylic acid copolymers: Copolymers of methyl methac-rylate (MMA) and ethyl acrylate (EA) as ester componentswith methacrylic acid (MA) are used for enteric coatings.Their enteric effect is attributed to the presence of carboxylicgroups that are transformed to carboxylate in the pH range of5 -- 7 by salt formation with alkali or amines. In pure waterand dilute acids they form a water-insoluble film which isresistant to gastric juice. Further, due to their low permeabi-lity to water vapor, an effective isolating layer is formed.The dissolution pH of the copolymer depends primarily onthe content of carboxylic groups; poly (MA-MMA) 1:1(Eudragit L) dissolves at > pH 6, poly (MA-MMA)
I CH2
CH3
C. +
C=O
OR
CH3
ExothermicC = CH2
C=O
OR
I CH2 CH2
CH3
C
C=O
OR
CH3
C
C=O
OR
Figure 1. Free radical polymerization started by initiator I [2].
CH3CH3H, CH3H, CH3
H, CH3
CH2CH2N(CH3)2HCH3, C2H5CH3, C2H5
H
CH3CH3CH3H,CH3HCH3
CH3, C4H9CH3CH2CH2N(CH3)3
+Cl-
CH3, C2H5
CH3, C2H5
EL and SRL and RSNE 30D
L 30 D-55 andL 100-55
EudragitGrade
R1
R1
C CH2 CH2 CH2CH2C
C=O
OR4
C
C=O
OR2
C
C=O
OR4 n
C=O
OR2
R3 R1 R3
R2 R3 R4
Figure 2. Basic chemical structure of Eudragit and different grades.
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1:2 (Eudragit S) dissolves at pH above 7. When the ester com-ponent is replaced with ethyl acrylate (poly (MA-EA) 1:1;Eudragit L 100-55), the resulting film dissolves above pH 5.5.
Methacrylate ester copolymers: Methacrylate ester copoly-mers are neutral or weakly cationic polymers and are insolublein pure water, dilute acids, buffer solutions, or digestive fluidsover the entire physiological pH range. Eudragit E is acationic polymer based on dimethylaminoethyl methacrylate,butyl methacrylate, and methyl methacrylate. It is soluble ingastric fluid as well as in weakly acidic buffer solution (up topH ~ 5) [2]. The films prepared from poly (EA-MMA)2:1 (Eudragit NE 30 D) swell in water, show medium degreeof permeability, which is not dependent upon pH. The filmformed at room temperature is also soft and flexible. Intro-duction of hydrophilic quaternary ammonium groups bycopolymerization with trimethylamminoethyl methacrylatechloride (TMACl) modifies permeability of the methacrylateester copolymers. Films of poly (EA-MMA-TAMCl)1:2:0.2 (Eudragit RL) are more permeable and poly (EA-MMA-TAMCl) 1:2:0.1 (Eudragit RS) are less permeablethan Eudragit NE 30 D. The quaternary ammonium groupscan be titrated electrometrically in water after addition ofmercuric acetate [4,5].
3.2 Characterization of Eudragit polymersX-ray powder diffractogram of Eudragit L 100, S 100, RL andRS are presented in Figure 3. As evident from the figure, thediffractograms of all these Eudragit grades demonstrate ahalo indicating amorphous nature of the polymers. Differen-tial thermal analysis of these polymers shows a single thermalevent as glass transition temperature, which is characteristicfor the different grades of Eudragit (Table 2). FTIR spectrumof Eudragit L 100, S 100, RS and RL (Figure 4) showscarbonyl vibrations of ester group in the range of1734 -- 1728 cm--1
[6,7].
3.3 Physical properties of different Eudragit gradesOne among the significant factors in describing the physicalproperties of polymeric films is the glass transition tempera-ture (Tg), which is a function of molecular mobility of thepolymer chain segments. Tg has far reaching consequences,for example, for film formation, melt processing, and storageof finished formulation. As evident from Table 2, the Tg ofEudragit grades NE is ~ 9� C, Eudragit E ~ 48� C, of entericpolymers (Eudragit L or S) is > 150� C, and insolublepolymethacrylates is ~ 55� C. A plasticizer in a film coatingformulation lowers the Tg of polymer by reducing the inter-molecular interaction between polymer chains and increasesthe flexibility of the resulting film. For obtaining properdegree of suppleness, 10% plasticizer is recommendedfor the insoluble grades and 40% plasticizer is needed forenteric grade, while no plasticizer is required for gastrosolublemethacrylate polymers [8]. Citrate esters, polyethyleneglycol 6000 or polypropylene glycol have been reported toeffectively plasticize polymethacrylate polymer films [9,10].
In addition to the above, another important polymer prop-erty playing decisive role in special applications is water vaportransmission rate (WVTR), which influences the storage stabi-lity of moisture sensitive formulations. In comparison tohydroxyl propyl methyl cellulose (showing WVTR 900 g/m2.day), polymethacrylate polymers demonstrate effective mois-ture barrier property (WVTR ~ 100 -- 350 g/m2.day) aspresented in Table 2 [2].
4. Coating methodologies used for Eudragit
Eudragit polymers are widely used as coating materials inorder to achieve either modification of drug release behavioror taste masking. For the purpose of coating, polymeric filmsare generally applied to the solid dosage forms using the sprayatomization technique. Traditionally, the polymethacrylatepolymers are generally dissolved in organic solvents likeisopropanol and acetone. The organic coating dispersionsare generally turbid and disturb the coating process. Additionof small amount of water is advised to improve the appearanceof the organic coating dispersion [8]. In addition, ready-to-useaqueous dispersions of many Eudragit grades are also com-mercially available. The solid core materials are often pre-heated in the coating equipment prior to the coatingprocess. To reduce the stickiness and minimize agglomerationof the coated substrates, anti-adherent compounds are gener-ally included in the coating formulations and talc is one ofthe most common anti-adherent. Studies have shown thattalc may cause increase in drug dissolution, presumably byforming cracks in the coating [11].
While organic solvent film-coating technology suffers fromtoxicological, environmental, cost, and safety-related disad-vantages [12], the aqueous-based coating technology is associ-ated with the limitations of slow drying rate of coating, highenergy input, possibility of microbial contamination, andstability issues with water-sensitive drugs [13]. Recently, vari-ous dry coating techniques for pharmaceutical products havebeen widely investigated as an alternative to liquid-basedcoating and these techniques have been applied for coatingwith Eudragit polymers also.
. Compression coating: Mixture of Eudragit RS PO and S100 was applied as seal coat on tablets to achieve con-stant rate-regulated release. Polymer coating was shownto be porous, allowing diffusion medium to enter thecore tablets and NMR analysis revealed diffusion ofwater into compression coated tablets [14].
. Modified fluidized bed Wurster process: Used to coatpellets with different formulations of Eudragit RS, ethylcellulose, and shellac so as to achieve sustained anddelayed release [15]. The process, however, is basedupon utilization of small amount of liquid plasticizerof polymer solution to facilitate film formation.
. Dry powder coating: Applied to coat tablets with Eudragitpolymers, for example, Eudragit E PO [16], Eudragit
*Not possible to determine Tg value for Eudragit S 100 and L 100, because of overlapping with the damage of the functional groups at temperatures of more
than 150�C.zIncludes the minimum film forming temperature of aqueous dispersion.
TEC: Triethyl citrate.
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RS/RL [17], and Eudragit L 100-55 [18]. In these processes,some polymers with higher glass transition temperature(Tg) like Eudragit RS, Eudragit L and Eudragit L100-55 were pre-plasticized with liquid plasticizer usinghot-melt extrusion prior to coating in order to lowerdown Tg so as to generate binding force at certain opera-ting temperature. Powder adhesion to the tablet isimproved by a partially melted polymer that generatesbinding force between particles and tablet surface.
. Electrostatic spray powder coating: Used with Eudragitpolymers, namely Eudragit RS and Eudragit E, asclaimed in several US patents by Phoqus Ltd. The coatingpowder was obtained by wet granulation followed byfluid bed drying and micronization using fluid energymill. Both the sides of tablets were coated separately usingspecialized equipments. Polymer particle fusion was com-pleted by curing with IR radiation [19]. The said processhas been later shown to exhibit difficulties in coatingtablets with well-defined edges [20].
. A modified coating process based on creation of electri-cal field by an electrostatic charging gun and groundedsubstrate to assist deposition of charged powder particleshas also been reported for coating tablets with EudragitRS and RL [21].
These solvent free coating processes, however, need to bemodified to obtain optimized coating [13].
5. Registered products containing Eudragit
A number of formulations employing Eudragit as coatingpolymer are being marketed as registered products and thesehave been compiled in Table 3.
6. Safety profile of Eudragit
Eudragits, owing to their stability in the presence of digestiveenzymes and body fluids, are known as non-biodegradable
Eudragit L 100
Eudragit S 100
Eudragit RL
Eudragit RS
Figure 4. FTIR spectra of different Eudragit polymers. Eudragit L 100, S 100, Eudragit RL and RS.
Eudragit�: a technology evaluation
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polymers. Eudragit E, basic methacrylate polymer, has beendemonstrated to be non-toxic and its properties moderatedgreatly by its lack of absorption as a result of the large effectivemolecular weight [22]. Detailed studies of toxicokinetics, acuteand subchronic oral toxicity, genotoxicity, and reproductivetoxicity of Eudragit E confirm absence of significant toxicityby external and oral routes of exposure. Based on thesereports, it has been proposed that Eudragit E is GRAS(Generally Regarded As Safe) on the basis of scientific proce-dures, as discussed at 21 CFR, Section 170.30, with regard toits use as direct and indirect food ingredients [22]. Similarly,the median lethal dose (LD50) of anionic methacrylate copo-lymer (Eudragit FS 30 D) in male and female Sprague-Dawley rats of CD(SD)BR strain was found to be in excessof 2,000 mg/kg body weight [23]. No-Observed-Adverse-Effect-Level (NOAEL) was found to be 400 mg/kg bodyweight/day in short term toxicity study conducted for28 days on male and female Beagle dogs [24], while the samehas been reported as 1,500 mg/kg body weight/day in sub-chronic oral toxicity study conducted for 26 weeks on maleand female Sprague-Dawley rats [25]. The in vitro cellmutation assay has demonstrated non-mutagenicity of thepolymer [26].Methacrylate copolymers are listed in the German Rote
Liste and are being used in pharmaceutical preparations.In USA, various grades of Eudragit are approved and listedin US FDA’s “Inactive Ingredients for Approved DrugProducts” list with the maximum potency of these gradesspecified with respect to the particular use [27]. Maximumpotency of different Eudragit grades for some of the impor-tant applications is compiled as Table 4. The polymetha-crylates are included in nonparentral medicines licensed inthe UK [3].
7. Applications of Eudragit in colon-specific/enteric-coated delivery system
Eudragits are extensively employed as pH-dependent coatingpolymers in order to attain either enteric effect or colontargeting of drugs. The pH-dependent systems are conven-tionally designed on the generally accepted view that pH ofthe human gastrointestinal tract increases progressively fromstomach (2.0 -- 3.0) to small intestine (6.5 -- 7.0) to colon(7.0 -- 8.0) [28] (though it has been reported that pH dropsslightly in colon and is highest in ileocecal junction [29]).Thus, it is expected that the polymer used as coating materialfor colon targeting should be able to withstand lower pHvalue of upper gastrointestinal tract and disintegrate at neutralor slightly alkaline pH of terminal ileum, preferentiallyileocecal junction.
Eudragit with its ensemble of polymer grades availablewhich exhibit a range of dissolution pH profile offer an ingen-uous method to avoid drug release in upper part of gastroin-testinal tract. The most commonly employed Eudragitgrades include Eudragit L 100 and S 100. Eudragit L dissolvesat pH > 6 and is used for enteric coating, whereas Eudragit S,which dissolves at pH > 7 (attributed to the presence of higheramount of esterified groups in relation to carboxylic groups) isused for colon targeting. Replacement of the methyl acrylatewith ethyl acrylate in Eudragit L led to introduction of Eudra-git L 100-55, which dissociates above pH 5.5. On the otherhand, increasing the proportion of esterified group in thepolymer from 50% in Eudragit L to 90% led to introductionof Eudragit FS 30 D, which is available as aqueous dispersionand shows dissolution at pH about 6.8 [2,30].
The use of Eudragit S was first described by Dew et al. forthe targeted delivery of drug, for example, 5-amino salicylic
Table 3. Marketed products based on Eudragit as coating polymer.
S.No. Active ingredient Trade name Manufactured by Coating polymer Dissolution pH
1 Sulfasalazine Colo-pleon Sanofi-Aventis Eudragit L 100-55 5.52 Mesalazine Claversal
Dr. Falk PharmaGSK AustraliaDr. Falk PharmaCosmo PharmaceuticalsCosmo PharmaceuticalsTeva PharmaceuticalSandozSalix Pharmaceuticals
Eudragit L 100Eudragit S 100Outer coat combination ofEudragit L 100 and S 100; innercoat of Eudragit S 100Eudragit L 100Eudragit L 100Eudragit L 100Eudragit S 100Eudragit S 100Eudragit S 100Eudragit S 100Eudragit L 100
> 6.0> 7.0> 7
> 6.0> 6.0> 6.0> 7> 7> 7> 7> 6.0
3 Budesonide Entocort
Budenofalk
Prometheus Lab.
Dr. Falk Pharma
Drug pellets in ethyl cellulose coatedwith Eudragit L 100-50Eudragit L 100 & Eudragit S 100
5.5
6 -- 7
4 Beclomethasonedipropionate
Clipper Chiesi Pharmaceuticals Eudragit L 100/55 5.5
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acid (5-ASA) in colitic patients, wherein dosage form disinte-gration and drug release was observed in distal gut [31,32]. Theresults from these studies provided the basis for the develop-ment and eventual commercialization of a number of modi-fied release products (Table 3). The colon-targeted drugdelivery systems using Eudragit have been described for anumber of drugs like insulin [33,34], prednisolone [35], campto-thecin [36], naproxen [37] and cyclosporine [38]. However, somein vivo reports revealed that the use of Eudragit S (which dis-solves at pH > 7) alone is not suitable for colonic delivery [39].In order to overcome the problem, it was shown that a propercombination of polymer Eudragit S 100 and Eudragit L100 ensures that the release of drug from formulation willoccur even when the pH value of the gastrointestinal tractdoes not reach more than 6.8 [40]. The combination of thesetwo polymers ensures that the coating begins to dissolve onentering small intestine, although thickness of coating pre-vents complete dissolution of the film and breakdown of thecapsule until further down the gut. Scintigraphic evaluationof the system in healthy volunteers has demonstrated colontargeting success rate of 90% [39].
It was shown through in vitro release studies that thesepolymers (used alone or in combination) exhibit excellentprotection in gastric pH followed by gradual or suddenrelease in alkaline environment in different pH conditions(6.0 -- 7.4). Some coated formulations, based on EudragitFS 30 D, have shown to resist disintegration/dissolution inupper gastrointestinal tract but have been reported to disinte-grate after colonic arrival [41-43]. However, studies in humanvolunteers have confirmed that since pH drops from 7.0 atterminal ileum to 6.0 in ascending colon, such systems some-times fail to release the drug [44]. The use of polymers thatrelease the drug at higher pH values (> 7.0) may fail to givereproducible results, since pH in the lower gastrointestinallumen (ileum and colon) may fail to exceed the dissolutionpH of the polymer in some patients, for example, in the
case of inflammatory bowel disease [45]. Therefore, coatedsystems, in general, may suffer from the drawback of non-reproducible release in vivo. Extensive studies carried out bysome research groups in the recent past have shown thattablets coated with Eudragit polymers sometimes demon-strated erratic performance in vivo, and tablets may fail todisintegrate inside the human body [46,47]. This has beenpreviously attributed to the narrow pH gradient between thesmall and large intestine, intersubject variability in gastroin-testinal pH, residence time of dosage form at ileocecal junc-tion, pH changes, that occur in diseased conditions andfasted or fed states resulting in variable performance of thesesystems [48].
In view of the aforesaid facts, it has been gradually appreci-ated that the conventional colonic delivery system based onlyon Eudragits may not be reliable in vivo because of the inher-ent variability of pH and emptying times from gastrointesti-nal tract. The combination of pH- dependent polymers withpolymers exhibiting time-based release has been proposed asone of the means for achieving controlled release of drugfrom the coated system [49]. Further, Eudragits in combina-tion with biodegradable guar gum [41] and starch [50] havealso been attempted and proven as triggers by microbial deg-radation for colon-specific release. Thus the focus has recentlyshifted to development of suitable targeted formulation basedon Eudragits in combination with other polymeric system.Some of the significant latest observations in the use ofEudragits based enteric/colon-targeted systems [33,34,42,47,50-68]
have been summarized in Table 5.A retrofit study of the Table shows that different methods
for imparting enteric/colon-targeted action have beenexploited. While some of the systems represent Eudragitcoated conventional unit dosage forms like tablets or cap-sules [47,51,52,54,56,58], recent trends indicate shift toward useof Eudragit-coated multiparticulate systems which includemicrospheres [57,59-63], pellets [50,55,64] or non-pariel seeds
Table 4. Maximum potency for different Eudragit grades for important applications [27].
S.No Grade of Eudragit Dosage form Maximum potency*
1 Eudragit L 100-55 Enteric-coated tabletsEnteric-coated pellets
17 mg28 mg
2 Eudragit 30 D Enteric-coated particles 27.9 mg3 Eudragit NE 40 D Capsules
containing drug [42,53]. Alternatively, colon-targeted formula-tion may be presented as Eudragit-based multiparticulatesystem, presented in the form of microcapsules prepared usingtechniques like double emulsion solvent evaporation, extru-sion spheronization, spray drying [33,34,68], as nanocapsulesprepared by nanoprecipitation [66], and as matrix [65] ormicrospheres [67] in combination with other suitable poly-mers. In addition to above, Eudragit S 100 based tabletshave been prepared by hot-melt extrusion to target drug deli-very to the colon and the drug release profiles of the extrudedtablets were found to fit both the diffusion and surface erosionmodels [70]. Recently, a double coating enteric system com-prising of inner coat (partially neutralized Eudragit L30 D-55 and an organic acid) and an outer coat (standardEudragit L 30 D-55) has been shown to achieve rapid drugrelease in proximal small intestine. The improved dissolutionof the system, attributed to increased ionic strength andbuffer capacity of its inner layer, has been demonstrated forin vitro studies, while in vivo study showed a more consistentdisintegration in proximal small intestine for the double-layered system as compared to conventional single entericcoating [71,72].
8. Application of Eudragit in sustainedrelease delivery system
By employing Eudragits as release-manipulating excipients, itis possible to achieve modified drug release either throughpolymeric coating on the drug reservoir core, or through theuse of polymeric matrix incorporating the drug itself.
8.1 Through sustained release coatingThe grades of Eudragit which are water insoluble, butswellable over the range of physiological pH are suitable forthe sustained release film coating applications and includeEudragit RL (highly permeable), Eudragit RS (low perme-able), Eudragit NE (permeable), and Eudragit NM (perme-able) [73]. Eudragit RL and RS have quaternary ammoniumgroups in the chloride salt form, and the dissociation of thesegroups in aqueous media is responsible for the swellability andpermeability of the polymers [74]. Eudragit RL includes agreater concentration of the quaternary ammonium groupsand the coatings made from this polymer are more permeablethan those which are made from Eudragit RS. The sustainedrelease Eudragit polymer can be used as coating materialsfor tablets [75], pellets and microspheres or capsules [74]. Often,Eudragit RS and (or) RL are used as coating materials tocreate sustained release drug forms from such active sub-stances like ibuprofen, indomethacin, nitrendipine, diltiazem,and others [74].
The mechanism of drug release from dosage forms coatedwith Eudragit RS and RL mixtures has been proposed to bethrough control of fluid permeation into the core and subse-quent dissolution and outward diffusion of the activesubstance [76]. The pores in the film have been shown to be
larger and the diffusion of the drug through these pores ishigher in Eudragit RL films than in Eudragit RS films.Drug diffusion has been shown to be dependent upon thesize of drug and steric effects [77] and also on ionic strengthand buffer species of the dissolution medium [78,79]. Further,the drug release from dosage forms formulated with EudragitRS and RL films has been shown to be pH independentattributed to ionization of quaternary ammonium groups atall pH levels occurring in the gastrointestinal tract.
The drug release from dosage forms coated by these poly-mers may be modified by addition of a wide range of otherexcipients. To increase the permeability of film, variouswater-soluble substances like sucrose, lactose and othersaccharides, starch, micronized cellulose, soluble celluloseethers, poly(vinylpyrrolidone), polyethylene glycol or itsderivatives, and fumed or precipitated silica can be added.For instance, the coating permeability from low permeableEudragit RS has been shown to increase with the addition ofinulin to the film [49]. Eudragit RL and RS, which are misciblein all proportions, have been used to adjust the drug release indifferent sustained release coating applications [73]. Additionof 200% talc to Eudragit RS/RL 30 D 95:5 plasticized withtriethyl citrate provided sustained release of drug and the dos-age form has been shown to be non-agglomerating, physicallystable, and without significant change in drug release afterstorage for a period of 3 months [80].
Eudragit RL and RS may also be combined with otherEudragit polymers to achieve the desirable dissolution profile.Eudragit RL 30 D and RS 30 D in combination withEudragit FS 30 D were used as coating materials to producesustained release pellets of 5-ASA for the colon targeting [74].Different ratios of Eudragit NE 30 D and Eudragit L30 D-55 were tested as the coating materials for drug-layeredbeads using verapamil-hydrochloride as the model drug. Thelag time observed with two suitable ratios of polymers, thatis, 75:25 and 80:20, was found to be 3 h and 6 h, respectively.Generally, the lag time increased and drug release decreasedwith increasing amount of Eudragit NE 30 D in the polymerblend [81].
The neutral Eudragit NE and NM polymer, commerciallyavailable as aqueous dispersion, could also be employed ascoating material to develop water-insoluble, permeable (pH-independent) formulation. The main difference between boththese dispersions is in the nature and content of emulsifier(Eudragit NE 30 D contains nonoxynol 100 (1.5% w/v) andEudragit NM 30 D contains polyethylene glycol stearyl ether(0.7%)). The films formed by these polymers are highly flexibleand do not need addition of a plasticizer. These films are insol-uble in gastrointestinal tract, show very low permeability and apH-independent swelling. For coating, anti-tacking agents areused to reduce the stickiness of the polymeric dispersion.Drug pellets sub-coated with ethyl cellulose and outer coatedwith Eudragit NE 30 D (containing small amount of drug)have demonstrated initial immediate-release of the drugdispersed in the outer coat and subsequently the desired
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sustained release of the drug from the pellets [82]. Stabilityproblems have been reported with the nonoxynol 100, in theform of crystallization of the surfactant upon storage at roomtemperature leading to increase in drug release rate [83].
8.2 Through swellable matrixEudragits are attractive matrix forming materials, due to theirhigh chemical stability, good compatibility properties, andlarge variety of available grades with different physicochemicalcharacteristics. Eudragit polymers are known to form aswellable matrix, wherein drug release is controlled by conti-nuously changing dimension of the diffusive barrier. Thisbarrier is the layer thickness externally formed on the matrixthat controls active substance transport through it. Theswellable matrices are examples of typical moving boundaryrelease systems. Matrix tablets containing Eudragit polymercan be manufactured by direct compression [84], wetgranulation [85] or melt extrusion [86].Direct compression has been extensively utilized as a
method for the preparation of Eudragit-based matrix tablets.Ceballos and co-workers prepared extended-release theophyl-line matrix tablets by a direct compression of drug and differ-ent pH-dependent (Eudragit L 100, S 100 and L 100-55) andtime-dependent (Eudragit RL PO and RS PO) polymercombinations. Matrix tablets based on L 100/RL PO and L100/RS PO mixtures gave the best results, displaying thehighest percentage of theophylline release and the matrix for-mulation allowed to obtain the more regular release profiles.This was achieved by the combination of the good erodibleproperties of L 100 with the swelling properties of RL POand RS PO polymers [87]. Colo and co-workers reportedthat compressed matrix tablets based on a pH-sensitive poly(ethylene oxide) and Eudragit L 100 compounds ensured acomplete release of the active substance during the transitfrom stomach to jejunum, unaffected by gastric pH fluctua-tions. Release in the gastric fluid was controlled by matrixswelling and/or drug dissolution, whereas matrix dissolutioncontrolled release in simulated jejunum fluid [88]. Inert matrixtablets of carteolol hydrochloride can be prepared fromEudragit RS as a supporting material with different fillersand wetting liquids, which include mannitol, polyethyleneglycol 6000, and Emcompress as fillers and Eudragit L12.5 as a wetting liquid. The two-phase release profile hasbeen accounted for as the release of a drug on the surface ofa tablet and the particles of the drug which are not completelysurrounded by the Eudragit, during the first phase and therelease of drug contained in the inert matrix during the secondphase [89].Melt extrusion as a method for producing the sustained
release pellets of poly (meth) acrylates is practicable since Eudra-gits are thermoplastic polymers, their physiochemical propertiessuch as melt viscosity, glass transition temperature, and temper-ature stability are ideal for use in melt extrusion [90-93]. Further,melt extruded matrix systems provide a strong controlled releaseeffect due to very dense structure and molecular dispersion of
the drug in polymer [94]. Based on low glass transition temper-ature of Eudragit RL and RS, these polymers can be processedwithout plasticizer. However, to enable even lower melt extru-sion temperature or less shear stress, plasticizer such as triethylcitrate, triacetin, dibutyl sebacate, or polyethylene glycol6000 can be used. As solid state plasticizer, citric acid was iden-tified for Eudragit RS as effective plasticizer [95]. In sustainedrelease applications, the influence of plasticizer type and con-centration on dissolution properties needs to be ensured. Forsolubility enhancing formulations, hydrophobic plasticizermay actually cause decrease in dissolution, whereas surfactantcan additionally improve solubility enhancing effect.
9. Applications of Eudragit in taste maskingand protective system
Eudragit polymers have been investigated for their possibleapplications in taste masking formulations and as protectiveformulation. Particularly cationic Eudragit E is well suitedfor taste masking applications formulated as fast dissolvingtablets. Due to presence of tertiary amino group as functionalunit, it forms films that are swellable and permeable, yet insol-uble, at pH 5 or higher, but dissolves rapidly by forming saltsat acidic pH values lower than 5. This polymer can preventthe release of the delivered drug in saliva (pH 6.8 -- 7.4) andreadily dissolves in gastric fluid (pH 1.0 -- 1.5) [96]. Alterna-tively anionic Eudragit LD 30 D-55 and cationic RL/RS30 D also have taste masking properties. Since these polymershave other specific functionalities (gastro-resistance or retar-dation) the polymer application is advised to be used as lowas possible [2]. Small particles such as crystals, granules, andpellets were coated with aqueous dispersions of methacrylicacid and methacrylic ester copolymers (Eudragit RL 30 D,RS 30 D, L 30 D-55, and NE 30 D) for taste masking andcompressed into fast dissolving tablets [97]. The fast dissolvingtablets, containing the taste-masked granules of pirenzepineHCl or oxybutynin HCl, were prepared by coating the drugswith Eudragit E 100 using the extrusion method. Drug releasefrom these Eudragit E based granules was shown to be negli-gible even after 8 h at pH 6.8 and none of the six volunteersreported any bitter taste upon administration of the fastdissolving tablet [96]. Taste-masked immediate release micro-matrix powders were formed by spray drying the drug andcationic copolymer with the drug: polymer ratio 1:4, prefera-bly 1:6 [98]. Drug release was shown to be < 5% in mediumrepresenting pH of saliva when linezolid was presented asmicrocapsules prepared by coacervation and subsequentmembrane coating on the microcapsules with Eudragit L30 D [99]. Indinavir loaded Eudragit E microparticles wereprepared by double emulsion/solvent evaporation and sensor-ing test by ten volunteers indicated that systems containing15% of the drug displayed acceptable taste, though drugloading as high as 90% was possible [100].
Further, Eudragit E coatings are also characterized by lowwater permeability and this polymer has been demonstrated
S. Thakral et al.
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to be an effective moisture protective film coating [101]. Bleyand co-workers determined glass transition relative humidityfor different polymers including Eudragit E through a combi-nation of differential scanning calorimetry and dynamic vaporsorption techniques and showed that this polymer remains inglassy state in the moisture protective film coatings [102]. Caoand co-workers reported effective moisture protection of silicaparticles when coated with the novel Eudragit E aqueousdispersion [103]. However, some of the studies have questionedthe effectiveness of low permeable Eudragit E barrier filmin the actual prevention of moisture-related deterioration ofdrugs using aspirin as model drug [104].
10. Incompatibilities associated with Eudragit
Though Eudragit polymers are regarded as chemically stable,incompatibilities of Eudragit polymers with few active ingre-dients have been documented in literature. As an example,incompatibility of Eudragit RS and RL with diflunisal, flurbi-profen, and piroxicam has been reported. It has been shownthat, except for mechanical dispersion, these drugs interactedwith Eudragit matrices by virtue of electrostatic interactionswith the ammonium groups present in the polymer [105,106].Physical and chemical interaction with the carboxylic groupof ibuprofen has been reported to occur because of electro-static interactions and/or hydrogen bonding with the quater-nary ammonium groups in Eudragit RL. This probablyinhibits uniform dispersion of the drug in the polymernetwork and ultimately affects the drug loading and releaseprofile in vitro and in vivo [107]. Through diffuse reflectanceinfrared Fourier transform spectroscopy, mild interaction,such as hydrogen bonding, has been suggested betweenprotonated tertiary amine group of the ranitidine and afunctional group on the Eudragit E 100 polymer [108].
Incompatibilities can also occur with certain polymethacry-late dispersions depending upon ionic and physical propertiesof the polymer and solvent. For example, coagulation may becaused by soluble electrolytes, pH changes, some organicsolvents, and extremes of temperatures. Dispersion of Eudra-git L 30 D, RL 30 D, L 100-55 and RS 30 D are incompat-ible with magnesium stearate (thickening or coagulation),though magnesium stearate contained in tablets does notaffect film properties [3,109]. Solid polymethacrylates andorganic solution are generally more compatible thanaqueous dispersions.
11. Conclusions
The present review shows that Eudragit represents a group ofsynthetic polymethacrylate copolymers, used as functionalexcipient in various pharmaceutical dosage forms. Eudragitpolymers, commercially available as granules, powder, organicsolution, or aqueous dispersions, have been widely used ascoating materials in order to achieve either modification ofdrug release behavior or taste masking. The incompatibilities
between Eudragit polymers (mostly aqueous dispersions)and active ingredients are few and defined. The safety associ-ated with use of Eudragits makes them attractive candidatesfor optimizing the existing dosage forms and developing thenew ones.
12. Expert opinion
Polymers have played indispensable role in pharmaceuticaldevelopment and manufacturing by facilitating developmentof robust medicinal products which deliver the drug at desiredsite of action in optimum therapeutic concentration. Whilenatural polymers (like pectin, shellac, starch) are biocompati-ble, some are expensive to produce and refine and also sufferfrom batch to batch variability in terms of physicochemicalproperties, based on source of raw materials. On the otherhand, synthetic polymers have excellent reproducibility andhence have clear advantage over natural polymers. Eudragitsrepresent group of polymethacrylate based polymers, con-taining methacrylic acid and methacrylic or acrylic esters ortheir derivatives in varying proportions. Being a syntheticpolymer, Eudragits display good reproducibility and otheradvantages associated with synthetic polymers. Further, theseare regarded as non-biodegradable, non-absorbable, andnon- toxic functional excipients, thus circumventing issuesaccompanying synthetic polymers.
Anionic Eudragits, represented by Eudragit L andEudragit S, have been extensively employed as coating mate-rial to evade drug release in stomach and facilitate the releasein small intestine or in the colonic regions. A number ofproducts based on Eudragit S alone or on a combination ofEudragit L and S are already in the market. The productshave been launched based on success stories demonstratingdosage form disintegration and drug release in distal gut.However, some recent studies have highlighted variability inthe performance of some marketed preparations and in fewcases, failure of dosage form to release the drug, which amongother factors, have been attributed to pH being less than 7 inthe ascending colon. Various strategies have been proposed toovercome this limitation, which includes the use of EudragitFS rather than Eudragit S (threshold dissolution pH of formerbeing 6.8 rather than 7), use of combination of Eudragit Land Eudragit S to facilitate drug release in intestinal environ-ment of pH less than 7, combination of Eudragit basedpH-mediated release with either pre-programmed time-basedor microflora-based release mechanisms utilizing suitablepolymers. Further, with the recent trend toward shiftingfrom single-unit to the multiple-unit design, many moresuccess stories employing Eudragit for colon targeting areexpected in the coming future.
Neutral Eudragit polymers RL and RS are considered to beimportant functional excipients to achieve sustained drugrelease. These two polymers demonstrate contrastinglydistinct release profiles and can be mixed in any proportionsto adapt permeability of coating to technological and
Eudragit�: a technology evaluation
Expert Opin. Drug Deliv. (2013) 10(1) 145
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pharmacokinetic requirements. However, processing of thesepolymers is known to be associated with tackiness, whichis frequently circumvented using talc. Use of talc in coatingformulations is known to be associated with processinglimitations, like clogging of spray nozzles, incompatibilitywith certain drugs. Agglomeration and sticking of pelletshave been demonstrated with the use of high curing tempera-ture used in the coating. This ultimately led to the damageto film coating and faster drug release. These processingdifficulties need to be optimized before use of polymer insustained release formulation transforms into industrialapplication.Cationic Eudragit E finds applications for taste masking
of bitter drugs in the formulation of fast dissolving tablets.The polymer prevents release of the delivered drug in thenear neutral saliva and readily dissolves in the acidic gastric
environment. For the purpose, it needs to be ensured thatthe dosage form is entirely coated and that the coating’s layerthickness is quite sufficient to prevent drug dissolution insaliva and mask the taste.
To summarize, Eudragits are nontoxic synthetic polymersproviding adequate scope for manipulating release profilethrough the use of different grades in combination. Certainprocessing difficulties and few incompatibilities with activeingredients need to be taken care of before utilizing them asfunctional excipient in the formulation of modified releasedosage form.
Declaration of interest
The authors state no conflict of interest and have received nopayment in preparation of this manuscript.
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AffiliationSeema Thakral1, Naveen K Thakral2 &
Dipak K Majumdar†3
†Author for correspondence1GVM College of Pharmacy,
